Derivatives of 5-carbamoyloxymethyl-3-substituted-2-oxazolidinones, process of preparation thereof and therapeutic application

ABSTRACT

A compound of the formula ##STR1## .[.in which R is H, halogen, alkyl having 1 to 4 carbon atoms or trifluoromethyl, and R 1  and R 2  each is H or dialkylaminoalkyl or together with N comprise methylpiperazino..]. .Iadd.in which (1) .Iadd. ##STR2##.Iaddend. is -NH 2  and R is H, m-CH 3 , o-CF 3 , m-Cl, p-Cl, m-Br, m-F, p-F, o-F, p-CH 3  or m-CH 3 , or .Iadd. ##STR3##.Iaddend. and R is H, m-CF 3  or m-F, or .Iadd. ##STR4##.Iaddend. and R is H, m-CF 3  or m-F. 
     The compound is prepared by treating the corresponding 5-hydroxymethyl compound with ammonia or an amine in the presence of phosgene. 
     The compounds possess anti-depressive, myorelaxing, tranquilizing, sedative, analgesic, anti-convulsive, anti-pyretic, anti-inflammatory and uricosuric activities.

This application is related to our application Ser. No. 20,020, filedMar. 16, 1970 .Iadd.now abandoned. .Iaddend.

The present invention concerns novel derivatives of5-carbamoyloxy-methyl-3-substituted-2-oxazolidinone, their process ofpreparation and their therapeutic application.

The compounds according to the present invention correspond to thegeneral formula: ##STR5## .[.in which:.]. .[.R is a hydrogen atom, ahalogen atom, an alkyl radical having 1 to 4 carbon atoms or atrifluoromethyl radical; and.].

.[.R₁ and R₂ each represent a hydrogen atom or a dialkylaminoalkylradical, or together with the nitrogen atom to which they are attachedform a methylpiperazino radical..].

.Iadd.in which (1) .Iadd. ##STR6##.Iaddend. is --NH₂ and R is H, m-CF₃,o-CF₃, m-Cl, p-Cl, m-Br, m-F, p-F, o-F, p-CH₃ or m-CH₃, or .Iadd.##STR7##.Iaddend. and R is H, m-CF₃ or m-F, or .Iadd. ##STR8##.Iaddend.and R is H, m-CF₃ or m-F.

The process for the preparation of the compounds according to thepresent invention comprises treating an oxazolidinone of the generalformula: ##STR9## in which R has the same significance as in Formula I,with phosgene in the presence of ammonia or an amine of formula:##STR10## in which R₁ and R₂ have the same significance as in Formula I.

The oxazolidinone of Formula II is prepared by cyclising, by the actionof ethyl carbonate, a 1-phenylamino-2,3-propanediol of the generalformula: ##STR11## in which R has the same significance as in Formula I.

The following preparation is given, by way of nonlimitative example, toillustrate the present invention.

EXAMPLE

5-carbamoyloxymethyl-3-m-trifluoromethylphenyl- 2-oxazolidinone (CodeNo. 68175).

(1) Preparation of5-hydroxymethyl-3-(m-trifluoromethylphenyl)-2-oxazolidinone (Code No.68121).

59 g. of 1-(m-trifluoromethylphenylamino)-2,3-propanediol and 118 g. ofethyl carbonate are introduced into a distillation apparatus. Themixture is progressively heated to about 110° C. when dissolution isobtained. Then, 12 ml. of 5% solution of sodium methylate in methanol isadded thereto. The distillation of the ethanol formed in the course ofthe reaction is then observed. Upon completion thereof, any excess ethylcarbonate is removed under reduced pressure; the solid residue obtainedis crystallised in isopropyl ether.

Melting point=80° C.

Yield=80%.

Empirical formula=C₁₁ H₁₀ F₃ NO₃.

Elementary analysis.--Calculated (percent): C, 50.58; H, 3.86; N, 5.36.Found (percent): C, 50.74; H, 3.76; N, 5.56.

(2) Preparation of 5-carbamoyloxymethyl-3-m-trifluoromethylphenyl)-2-oxazolidinone.

300 ml. of a 20% solution of phosgene in toluene is rapidly added to asolution of 100 g. of5-hydroxymethyl-3-(m-trifluoromethylphenyl)-2-oxazolidinone in 250 ml.of benzene. 63 g. of N,N-diethylaniline is then slowly added theretowith agitation. The hydrochloride which precipitates is dried and theclear organic solution also obtained is treated with a rapid current ofgaseous ammonia. The solution is then treated with water, decanted andthe organic phase is concentrated. The solid residue obtained iscrystallised in absolute ethanol.

Melting point=123° C.

Yield=50%.

Empirical formula=C₁₂ H₁₁ F₃ N₂ O₄.

Elementary analysis.--Calculated (percent): C, 47.37; H, 3.64; N, 9.21.Found (percent): C, 47.50; H, 3.86; N, 9.39.

The following Table I lists a certain number of intermediate compoundsof Formula II prepared according to the first part of the above example,and Table II enumerates a certain number of compounds of Formula Iprepared according to the second part of the above example.

                                      TABLE I                                     __________________________________________________________________________     ##STR12##                                                                                               Elementary analysis                                Code    Empirical                                                                            Mol.                                                                              M.P.,                                                                             Yield,                                                                            Calculated                                                                             Found                                     No. R   formula                                                                              Wt. ° C.                                                                       percent                                                                           C  H  N  C  H  N                                   __________________________________________________________________________    67360                                                                             H   C.sub.10 H.sub.11 NO.sub.3                                                           193.20                                                                            129 75  62.16                                                                            5.74                                                                             7.25                                                                             63.20                                                                            5.87                                                                             7.40                                68292                                                                             m.F.                                                                              C.sub.10 H.sub.10 FNO.sub.3                                                          211.19                                                                            96  87  56.87                                                                            4.77                                                                             6.63                                                                             56.88                                                                            4.92                                                                             6.79                                69155                                                                             p.F.                                                                              C.sub.10 H.sub.10 FNO.sub.3                                                          211.19                                                                            116 68  56.87                                                                            4.77                                                                             6.63                                                                             56.97                                                                            4.77                                                                             6.83                                69275                                                                             o.F.                                                                              C.sub.10 H.sub.10 FNO.sub.3                                                          211.19                                                                            94  60  56.87                                                                            4.77                                                                             6.63                                                                             56.75                                                                            4.73                                                                             6.67                                6922                                                                              p.Cl.                                                                             C.sub.10 H.sub.10 ClNO.sub.3                                                         227.64                                                                            104 55  52.75                                                                            4.43                                                                             6.15                                                                             53.01                                                                            4.53                                                                             6.05                                69204                                                                             p.CH.sub.3                                                                        C.sub.11 H.sub.13 NO.sub.3                                                           207.22                                                                            145 66  63.75                                                                            6.32                                                                             6.76                                                                             63.93                                                                            6.10                                                                             6.88                                69276                                                                             m.CH.sub.3                                                                        C.sub.11 H.sub.13 NO.sub.3                                                           207.22                                                                            76  70  63.75                                                                            6.32                                                                             6.76                                                                             63.70                                                                            6.43                                                                             6.78                                .[.69217                                                                          o.CH.sub.3                                                                        C.sub.11 H.sub.13 NO.sub.3                                                           207.22                                                                            64  69  63.75                                                                            6.32                                                                             6.76                                                                             63.71                                                                            6.37                                                                             6.88.].                             __________________________________________________________________________

                                      table ii                                    __________________________________________________________________________     ##STR13##                                                                                                     elementary analysis                          Code        Empirical                                                                              Mol.                                                                              M.P.,                                                                             Yield,                                                                            Calculated  Found                            No. R   Salt                                                                              formula  wt. ° C.                                                                       percent                                                                           C  H  N  Cl C  H  N  C.sub.1                 __________________________________________________________________________    6878                                                                              H   --  C.sub.11 H.sub.12 N.sub.2 O.sub.4                                                      236.22                                                                            130 50  55.93                                                                            5.12                                                                             11.86                                                                            -- 55.73                                                                            5.27                                                                             11.72                                                                            --                      6978                                                                              o.CF.sub.3                                                                        --  C.sub.12 H.sub.11 F.sub.3 N.sub.2 O.sub.4                                              304.22                                                                            135 --  47.37                                                                            3.64                                                                              9.21                                                                            -- 47.40                                                                            3.82                                                                              9.41                                                                            --                      68291                                                                             m.Cl                                                                              --  C.sub.11 H.sub.11 Cl N.sub.2 O.sub.4                                                   270.67                                                                            102 40  48.81                                                                            4.10                                                                             10.35                                                                            -- 48.80                                                                            3.88                                                                             10.22                                                                            --                      6902                                                                              p.Cl                                                                              --  C.sub.11 H.sub.11 Cl N.sub.2 O.sub.4                                                   270.67                                                                            120 74  48.81                                                                            4.10                                                                             10.35                                                                            -- 49.01                                                                            4.25                                                                             10.35                                                                            --                      6945                                                                              m.Br                                                                              --  C.sub.11 H.sub.11 Br N.sub.2 O.sub.4                                                   315.12                                                                            132 50  41.92                                                                            3.52                                                                              8.89                                                                            -- 42.01                                                                            3.72                                                                              9.06                                                                            --                      6901                                                                              m.F.                                                                              --  C.sub.11 H.sub.11 FN.sub.2 O.sub.4                                                     254.21                                                                            110 70  51.97                                                                            4.36                                                                             11.02                                                                            -- 51.93                                                                            4.44                                                                             11.13                                                                            --                      69254                                                                             p.F.                                                                              --  C.sub.11 H.sub.11 FN.sub.2 O.sub.4                                                     254.21                                                                            140 60  51.97                                                                            4.36                                                                             11.02                                                                            -- 52.07                                                                            4.34                                                                             10.82                                                                            --                      69263                                                                             o.F.                                                                              --  C.sub.11 H.sub.11 FN.sub.2 O.sub.4                                                     251.21                                                                             80 40  51.97                                                                            4.36                                                                             11.02                                                                            -- 52.16                                                                            4.34                                                                             10.94                                                                            --                      69252                                                                             p.CH.sub.3                                                                        --  C.sub.12 H.sub.14 N.sub.2 O.sub.4                                                      250.25                                                                            148 60  57.59                                                                            5.64                                                                             11,20                                                                            -- 57.40                                                                            5.56                                                                             11.40                                                                            --                      59237                                                                             m.CH.sub.3                                                                        --  C.sub.12 H.sub.14 N.sub.2 O.sub.4                                                      250.25                                                                            105 70  57.59                                                                            5.64                                                                             11.20                                                                            -- 57.40                                                                            5.44                                                                             11.13                                                                            --                      .[.69239                                                                          O.CH.sub.3                                                                        --  C.sub.12 H.sub.14 N.sub.2 O.sub.4                                                      250.25                                                                            126 35  57.59                                                                            5.64                                                                             11.20                                                                            -- 57.79                                                                            5.72                                                                             11.26                                                                            --.].                   __________________________________________________________________________     ##STR14##                                                                    __________________________________________________________________________    68327                                                                             H   --  C.sub.15 H.sub.21 N.sub.3 O.sub.4                                                      307.34                                                                             77 50  58.62                                                                            6.89                                                                             19.67                                                                            -- 59.18                                                                            7.14                                                                             -- --                          --  HCl C.sub.15 H.sub.22 Cl N.sub.3 O.sub.4                                                   313.80                                                                            168 90  52.40                                                                            6.45                                                                             12.22                                                                            -- 52.32                                                                            6.68                                                                             12.43                                                                            --                      6985                                                                              m.CF.sub.1                                                                        --  C.sub.16 H.sub.20 F.sub.3 N.sub.2 O.sub.4                                              375.34                                                                             78 40  51.20                                                                            5.37                                                                             11.20                                                                            -- 51.18                                                                            5.52                                                                             11.40                                                                            --                      69253                                                                             m.F --  C.sub.15 H.sub.20 FN.sub.3 O.sub.4                                                     325.33                                                                             78 35  55.37                                                                            6.20                                                                             12.92                                                                            -- 55.27                                                                            6.13                                                                             12.96                                                                            --                          --  HCl C.sub.15 H.sub.21 Cl FN.sub.3 O.sub.4                                                  361.80                                                                            140 --  49.79                                                                            5.85                                                                             11.62                                                                            -- 49.59                                                                            5.97                                                                             11.50                                                                            --                      __________________________________________________________________________     ##STR15##                                                                    __________________________________________________________________________    68306                                                                             H   --  C.sub.16 H.sub.21 N.sub.3 O.sub.4                                                      319.35                                                                             70 50  60.17                                                                            6.63                                                                             13.16                                                                            -- 59.98                                                                            6.42                                                                             13.36                                                                            --                          --  HCl C.sub.16 H.sub.22 ClN.sub.3 O.sub.4                                                    355.82                                                                            220 98  54.01                                                                            6.23                                                                             11.81                                                                            9.96                                                                             53.81                                                                            6.39                                                                             11.78                                                                            10.13                   6089                                                                              m.CF.sub.3                                                                        --  C.sub.17 H.sub.20 F.sub.3 N.sub.3 O.sub.4                                              359.34                                                                             66 --  52.71                                                                            5.20                                                                             10.85                                                                            -- 52.71                                                                            5.33                                                                             10.76                                                                            --                          --  Maleate                                                                           C.sub.21 H.sub.24 F.sub.3 N.sub.3 O.sub.4                                              503.43                                                                            120 80  50.10                                                                            4.81                                                                              8.35                                                                            -- 49.96                                                                            5.12                                                                              8.54                                                                            --                      69235                                                                             m.F --  C.sub.16 H.sub.20 FN.sub.3 O.sub.4                                                     337.34                                                                             75 31  56.96                                                                            5.98                                                                             12.46                                                                            -- 56.77                                                                            5.79                                                                             12.58                                                                            --                          --  HCl C.sub.16 H.sub.21 FN.sub.3 O.sub.4                                                     373.81                                                                            210 40  51.41                                                                            5.66                                                                             11.24                                                                            -- 51.33                                                                            5.46                                                                             11.26                                                                            --                      __________________________________________________________________________

the compounds of Formula I experimentally exert anti-depressive,myorelaxing, tranquillising, sedative, analgesic, anti-convulsive,anti-pyretic, anti-inflammatory and uricosuric activities. Moreover,their toxic effects on animals in the laboratory are little marked.

(I)--Anti-depressive properties

The compounds of Formula I are capable of opposing hypothermia and theptosis provoked by reserpine in the rat and the mouse, as well as theulcers provoked by reserpine in the rat. Moreover, they oppose thecatalepsy provoked by prochlorperazine in the art.

By way of example, several results obtained are listed in the followingtable:

                                      TABLE III                                   __________________________________________________________________________                 Ptosis                                                           Hypothermia  Rat     Mouse   Ulcers  Catalepsy                                Code     Effect, Effect, Effect  Effect, Effect,                              Number                                                                             Dose.sup.1                                                                        ° C.                                                                       Dose.sup.1                                                                        percent                                                                           Dose.sup.1                                                                        percent                                                                           Dose.sup.1                                                                        percent                                                                           Dose.sup.1                                                                        percent                              __________________________________________________________________________    6878 200 -3.4                                                                              200 53  200 55  200 60  --  --                                   68175                                                                              100 -4  --  --  100 85  --  --  --  --                                   6901 100 -2.4                                                                              100 50  100 60  100 55  200 2.9                                  68921                                                                              100 -3  100 60  100 50  --  --  --  --                                   6902 100 -2.7                                                                              100 45  100 50  --  --  --  --                                   6945 100 -2.5                                                                              100 55  100 45  --  --  --  --                                   69237                                                                              --  --  100 45  100 45  --  --  --  --                                   69252                                                                              --  --  100 50  100 50  --  --  --  --                                   6985 100 -2  --  --  --  --  --  --  --  --                                   69254                                                                              --  --  --  --  100 54  --  --  --  --                                   69263                                                                              --  --  --  --  100 50  --  --  --  --                                   __________________________________________________________________________     .sup.1 Expressed in mg./kg./P.O.                                         

(II)--Myorelaxing properties

The compounds of Formula I provoke in the mouse the loss of the rightingreflex and inhibit the traction reflexes and the maintenance on arotating rod.

By way of example, for the compound No. 68175, the Ed₅₀ in the tractiontest and also on the rotating rod is 130 mg./kg./P.O.

(III)--Tranquilising and sedative action

These effects are shown by a diminution of the exploration curosity inthe enclosure of an actimetric cage and of escape in an open field. Thecompounds of Formula I reduce the aggresiveness provoked by the passageof an electric current and lower the body temperature of animals. Thenarcotic effects of penthiobarbital are equally reinforced.

The results obtained with two compounds of Formula I are listed in thefollowing table:

                  TABLE IV                                                        ______________________________________                                                                   Potentialisation                                                              of penthio-                                        Actimetric     Evasion test                                                                              barbital                                           Code           Effect,       Effect,      Effect,                             Number Dose.sup.1                                                                            percent Dose.sup.1                                                                          percent                                                                             Dose.sup.1                                                                           percent                             ______________________________________                                        6878   --      --      --    --    180    50                                  68175  95      50      200   50    100    60                                  ______________________________________                                         .sup.1 Expressed in mg./kg./P.O.                                         

(IV)--Analgesic activity

This activity is particularly pronounced against the painful stretchingprovoked in the mouse by the intraperitoneal administration of phenylbenzoquinone or acetic acid.

The results obtained with two compounds of Formula I are shown in thefollowing table:

                  TABLE V                                                         ______________________________________                                                    Protection against                                                            phenyl benzoquinone                                                             Dose in        Effect,                                          Code Number   mg./kg./P.O.   percent                                          ______________________________________                                        68175         62             60                                               6902          100            40                                               ______________________________________                                    

(V)--Anti-convulsive properties

The compounds of Formula I exert in the mouse an antagonism against thelethal effects of cardiazol, strychnine and nicotine. They equally showactivity against the tonic hyperextension of an excessive electricshock.

By way of example, the results obtained with several compounds ofFormula I are listed in the following table:

                                      TABLE VI                                    __________________________________________________________________________            Antagonism against-                                                           Cardiazol                                                                             Strychnine                                                                            Nicotine                                                                              Electric shock                                            Effect, Effect, Effect, Effect,                                   Code Number                                                                           Dose.sup.1                                                                        percent                                                                           Dose.sup.1                                                                        percent                                                                           Dose.sup.1                                                                        percent                                                                           Dose.sup.1                                                                        percent                                   __________________________________________________________________________    6878    --  --   43  60 --  --  --  --                                        68175    90 50   20  50 100 90  100 80                                        6901    --  --   50  90 --  --  --  --                                        68291   --  --  100 100 100 90  --  --                                        6902    100 60  100 100 100 80  --  --                                        6945    --  --  100 100 100 75  --  --                                        .[.69239                                                                              --  --  --  --  100 40  --  --.].                                     69237   --  --  100  80 --  --  --  --                                        69252   --  --  100  80 --  --  --  --                                        6985    --  --  --  --  100 70  --  --                                        69254   --  --  100 100 100 55  --  --                                        69263   --  --  100  90 --  --  --  --                                        __________________________________________________________________________     .sup.1 Expressed in mg./kg./P.O.                                         

(VI)--Anti-pyretic action

This action is manifested by a diminution of the experimental feverprovoked by the administration of barm in the cat.

(VII)--Anti-inflammatory effect

The under-planatar oedema provoked in the rat by the administration ofcarraghenine is diminished by the compounds of the present invention.

The results obtained with two of the compounds of Formula I are shown inthe following table:

                  TABLE VII                                                       ______________________________________                                                                   Reduction of                                                    Dose in       the oedema,                                        Code Number  mg./kg./P.O.  percent                                            ______________________________________                                        68175        200           65                                                 68291        100           40                                                 ______________________________________                                    

(VIII)--Uricosuric action

After repeated oral administration in the rat, the compounds of FormulaI provoke an augmentation of the urinary elimination of uric acid.

In consequence of the results shown above, and the values appearing inthe following table, the difference between the pharmacologically-activedose and the lethal dose is sufficiently great to enable the compoundsof Formula I to be utilised in therapeutics.

                  TABLE VIII                                                      ______________________________________                                        L.D..sub.60 P.O. (mouse)                                                             Code No.:     Mg./kg.                                                  ______________________________________                                               6878          2,700                                                           68175         2,100                                                           6901          2,800                                                           68291         >3,200                                                          6902          1,500                                                           6945          >3,200                                                          .[.69239      >4,000.].                                                       69237         4,000                                                           69252         >4,000                                                          6985          1,350                                                           69254         2,500                                                           69263         3,400                                                    ______________________________________                                    

The compounds of Formula I are indicated in the case of depression andneurosis by depressive and anxious components. They equally possess afavourable effect against contractural and inflammatory pains, with orwithout hyperthermia.

They may be administered in the form of tablets and gelules containing50 to 250 mg. of active ingredient.

Hence, according to the present invention there is also provided atherapeutic composition comprising a compound of Formula I together witha therapeutically-acceptable carrier.

Several clinical tests to show the activity of the compounds of thepresent invention are given below:

EXAMPLE 1.--Compound No. 6901

1st observation: Mr. M. aged 46.

An intellectual, working in a scientific field of high precision, thisman was affected by a spasmodic stiff neck due to anxious andhypochondriac grounds. He complained of cervical pains which preventedhim from keeping his head upright and concentrating on his work. As aresult, he became apathetic, depressed and profoundly restless about hisfuture.

Compound No. 6901, in tablet form containing 100 mg. of activeingredient, was administered three times daily for 15 days. The cervicalpains disappeared and he was able to hold his head in an uprightposition. Besides this myorelaxant action, there is equally ascertaineda complete sedation of his depressive anxieties.

2nd observation: Mr. Z. aged 55.

Professional and financial worries were provoked by a reactive neurosis,manifesting itself by an important irritability making family life verydifficult. He complained as well as obstinate insomnia and particularlyof diverse symptoms characterised by extra-systoles and occasionally ofparoxysmic tachycardia, of globus epigastrus and of transient intestinaltroubles. His hands trembled uncontrollably. He sometimes had autolysisnotions.

Compound No. 6901 in tablet form containing 100 mg. of activeingredient, was administered daily for three weeks, brought the subjectback to a normal state, his hands no longer trembled, his sleep returnedto normal and he no longer suffered from cardiac or digestive troubles.His troubles disappeared and he was able to attack his commercialproblems with courage.

EXAMPLE 2.--Compound No. 68175

Observation: Mrs. A. aged 48.

This woman was in a pre-menopause phase. For two years, she complainedapart from menstrual troubles, exacerbated nervousness, interior tensionsensations and trouble with precordial striction. She also complained ofinsomnia and a certain pain in the legs in the sleeping position.

Compound No. 68175, in tablet form containing 100 mg. of activeingredient, was administered 3 times a day for 12 days.

The sedative and tranquillising action is rapidly manifested, causingthe irritability to disappear as well as the pain and insomnia.Simultaneously, the myorelaxant action was equally evidenced, as shownby the complete disappearance of the interior tension and the pain inthe legs. Moreover, her sleep returned to normal.

What we claim is: .[.1. A compound of the formula ##STR16## in which Ris hydrogen, halogen, alkyl having 1 to 4 carbon atoms andtrifluoromethyl, and and the pharmaceutically acceptable acid additionsalts thereof..]. .[.2. A compound as claimed in claim 1, in which R isa chlorine, bromine or fluorine atom..]. .Iadd.3. A compound of theformula .Iadd. ##STR18##.Iaddend. in which (1) .Iadd. ##STR19##.Iaddend.is --NH₂ and R is H, m-CF₃, o-CF₃, m-Cl, p-Cl, m-Br, m-F, p-F, o-F,p-CH₃ or m-CH₃, or .Iadd. ##STR20##.Iaddend. and R is H, m-CF₃ or m-F,or .Iadd. ##STR21##.Iaddend. and R is H, m-CF₃ or m-F, and thepharmaceutically acceptable acid addition salts thereof.